Inflammation is the reaction of living tissue to injury. During inflammation, a complex of cytologic and chemical reactions of affected blood vessels and adjacent tissues respond to an injury or abnormal stimulation caused by a physical, chemical or biological agent. Signaling agents are released, attracting tissue macrophages and white blood cells. Proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) are activated, giving rise to inflammation.
Proinflammatory cytokines such as TNF and IL-1 are mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure. In a study of patients presenting at a hospital with sepsis, a correlation was found between TNF and IL-6 levels and septic complications (Terregino, et al., Ann. Emerg. Med., 35:26 (2000)).
Many conditions are thought to be associated directly or indirectly with inflammatory injury, and many commonly used therapeutic methods may also result in inflammatory injury either directly or indirectly. Exemplary types of inflammatory injury include traumatic injury, ischemia, and ischemia and reperfusion. Ischemic injury, or injury following ischemia, includes cellular damage resulting from an ischemic insult, which can occur upon the restriction or cessation of the flow of oxygen to an organ or tissue, such as by blockage or disconnection of one or more blood vessels. Ischemia can occur gradually or rapidly and can be either warm or cold.
Ischemia and reperfusion (I/R) injury is a pathophysiologic process whereby hypoxic organ damage is accentuated following return of blood flow and oxygen delivery following ischemia. The pathophysiology of ischemia and reperfusion injury includes both direct cellular damage as the result of the ischemic insult as well as delayed dysfunction and damage resulting from activation of inflammatory pathways.
An event of ischemia, including ischemia with reperfusion, can be controlled or uncontrolled. Controlled events can occur in vivo, ex vivo, or in vitro, during therapeutic treatment, such as a surgical procedure, during organ transplantation, during investigatory research, or in any circumstance under which they are deliberately induced. Most common controlled events include surgical procedures such as vascular surgery and cardiac bypass, as well as organ transplantation. Uncontrolled events can arise gradually, such as by accumulation of plaque in a coronary artery, or rapidly, such as during acute illness or upon injury. Ischemia and reperfusion can be controlled or uncontrolled independently. In some cases, uncontrolled ischemia can be treated with controlled reperfusion, such as in revascularization of a myocardial infarct, or in resuscitative treatment of hemorrhagic and/or hypovolemic shock. In other cases, transient episodes of ischemia followed by reperfusion are encountered during controlled procedures such as solid organ transplantation or elective liver resection, when inflow occlusion or total vascular exclusion can be used to minimize blood loss.
Inflammatory injury due to trauma, ischemia, and/or reperfusion are associated with, for example, anaphylaxis, apoptosis, burn injury, bursitis, cardiopulmonary bypass surgery, cerebral infarction, circulatory shock, compartment syndrome, congestive heart failure, conjunctivitis, coronary angioplasty blood vessel attachment, coronary artery obstruction, crushing injury, dermatitis, diseases involving angiogenesis, frostbite, graft rejection, gram negative bacteria-mediated circulatory shock, gram positive bacteria-mediated circulatory shock, hemodynamic shock, hemorrhage, hemorrhagic shock, hyperoxic alveolar injury, hypersensitivity, kidney failure, limb attachment or reattachment, liver failure, mycobacterial infection, myocardial infarction, myocardial ischemia, nephrotic syndrome, organ attachment or reattachment, organ reperfusion, periarteritis nodosa, radiation damage, septic shock, solid organ transplantation, spinal/head trauma and concomitant severe paralysis, stroke, swelling occurring after injury, and systemic inflammatory response syndrome (SIRS).
Methods of treating and preventing inflammation are known in the art, including administration of pharmaceuticals such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDS), COX-2 inhibitors, or cytotoxic agents. An inhibitor of TNF production, HU-211, was shown to improve the outcome of closed brain injury in an experimental model (Shohami, et al, J Neuroimmunol. 72:169 (1997)). In an animal model, an IL-1 receptor antagonist was shown to inhibit fatty streak formation associated with atherosclerosis, a disease known to have an inflammatory component (Elhage et al., Circulation, 97:242 (1998)). U.S. Pat. No. 6,811,768 to Zapol, et al. describes the use of inhaled nitric oxide (NO) to decrease injury in pulmonary ischemia and reperfusion.
Preconditioning is another strategy for protection that has been studied extensively in many models of organ injury. By pre-exposing the organ to a minor stress at a pre-determined time point, preconditioning renders the organ less vulnerable to a subsequent injury. Previous efforts to precondition organs to ischemia and reperfusion have applied stimuli such as heat (Ishikawa, et al., J. Surg. Res. 97:178-184 (1999)), endotoxins including lipopolysaccharides (LPS) (Colletti, et al., J. Surg. Res. 57:337-343 (1994)), ischemia (Cavalieri, et al., Liver Transpl. 8:990-999 (2002)), and intermittent clamping (Murry, et al., Circulation, 74:1124-1136 (1986)). Preconditioning has also been undertaken using pharmacologic agents such as adenosine, IL-10, S-adenosyl-L-methionine, and cromakalim. See, e.g., Tsai, et al., Shock 21(3):195-209 (2004).
Despite the availability of certain regimens, treatments capable of diminishing inflammatory injury, as well as methods for preventing inflammatory injury and protecting an organ or tissue from injury, are needed.